Surgical Management of Painful Neuromas

Chronic pain can be severely disabling and represents a greatly underestimated public health problem. “Pain can kill. It can kill the spirit, vitality and the will to live,” said Joel Saper, MD and president of the American Headache Society, in response to law the US Congress passed into provision in late 2000, declaring the following decade (January 1st 2001 – 2011) as the Decade of Pain Control and Research. A critical goal of the Decade of Pain initiative was to maximize the public and professional understanding of pain and pain management. Approximately 20% of adult Europeans suffer from chronic pain of moderate to severe intensity, seriously affecting the quality of their social and working lives. Neuropathic pain is thought to be a particularly distressing chronic pain condition that is often under-diagnosed and under-treated. Neuropathic pain has been defined as pain arising as a direct consequence of a lesion or disease affecting the somatosensory system, and is often therapy resistant for reasons largely unknown. Pain intensity and duration are reported to be higher in comparison to chronic pain without neuropathic characteristics. Recently published studies involving epidemiological surveys in Europe suggested neuropathic pain to have a prevalence of 7–8% in the general population. Approximately 3-5% of all patients involved in peripheral nerve injury develop a symptomatic neuroma. In the Netherlands, there are approximately 3.5/100,000 or 580 new cases of neuropathic pain caused by traumatic or iatrogenic nerve injury every year

Stable isotope dilution assay for the accurate determination of mycotoxins in maize by UHPLC-MS/MS

A fast, easy-to-handle and cost-effective analytical method for 11 mycotoxins currently regulated in maize and other cereal-based food products in Europe was developed and validated for maize. The method is based on two extraction steps using different acidified acetonitrile–water mixtures. Separation is achieved using ultrahigh-performance liquid chromatography (UHPLC) by a linear water–methanol gradient. After electrospray ionisation, tandem mass spectrometric detection is performed in dynamic multiple reaction monitoring mode. Since accurate mass spectrometric quantification is hampered by matrix effects, uniformly [13C]-labelled mycotoxins for each of the 11 compounds were added to the sample extracts prior to UHPLC-MS/MS analysis. Method performance parameters were obtained by spiking blank maize samples with mycotoxins before as well as after extraction on six levels in triplicates. The twofold extraction led to total recoveries of the extraction steps between 97% and 111% for all target analytes, including fumonisins. The [13C]-labelled internal standards efficiently compensated all matrix effects in electrospray ionisation, leading to apparent recoveries between 88% and 105% with reasonable additional costs. The relative standard deviations of the whole method were between 4% and 11% for all analytes. The trueness of the method was verified by the measurement of several maize test materials with well-characterized concentrations. In conclusion, the developed method is capable of determining all regulated mycotoxins in maize and presuming similar matrix effects and extraction recovery also in other cereal-based foods

Spisulosine (ES-285) given as a weekly three-hour intravenous infusion: results of a phase I dose-escalating study in patients with advanced solid malignancies

Spisulosine is a marine compound that showed antitumor activity in preclinical studies. We report results of a phase I trial performed in patients with advanced solid tumors with the marine compound, with the aim to determine the maximum tolerated dose (MTD) of a weekly 3-h intravenous (iv.) infusion, and to evaluate the safety, efficacy, and pharmacokinetics (PK) of the compound. Two centers contributed 25 patients to the trial, and 7 dose levels were explored. In dose levels ranging from 4 to 128 mg/mA(2)/day, no dose-limiting toxicities (DLT) were observed. One patient had DLT at 200 mg/mA(2), a reversible grade 3 ALT increase. The MTD was not reached due to early termination of the Spisulosine trial program but is considered to be likely in the range of 200 mg/mA(2) for this schedule. Drug-related adverse reactions included mild to moderate nausea, pyrexia, injection site reactions, and vomiting. One case of grade 4 peripheral motor and sensory neuropathy associated with general weakness and pain was observed during treatment cycle 4 and possibly contributed to the death of the patient. Grade 3 laboratory abnormalities included anemia and lymphopenia and increases in liver enzymes (alkaline phosphatase, transaminases, and bilirubin). Objective responses were not observed, and only four patients had short-lasting stable disease (< 3 months). The PK data indicated a wide distribution, a long residence time, and dose proportionality of the agent. Hepato- and neuro-toxicity are schedule independent dose-limiting adverse events for this marine compound, as illustrated by this and other early clinical trials

How to Influence National Pride? The Olympic Medal Index as a Unifying Narrative

Elite sport is often regarded as one of the main vehicles for articulating national pride and stimulating national cohesion. In this article, we explore a variety of different notions of pride and nationality as related to success in elite sport. We present the results of a public survey, which measured some of the effects on national pride in the Netherlands, related to the men's European Football Championships, the Tour de France, Wimbledon and the Olympic Games in Beijing (all in the summer of 2008). The results suggest that a sense of belonging is a necessary condition that precedes rather than results from sport-related pride. This supports the notion of national pride being a rather stable characteristic of countries, notwithstanding specific situations (such as sport success) that may lead to minor and temporary fluctuations. There seems to be no empirical evidence for the - primarily quantitatively understood - concept of pride (as a 'bucket-notion'), which is often implicit to the political rhetoric used to increase sport funding with the aim of winning more medals to generate an increase in national pride. © The Author(s) 2010

Simultaneous pharmacokinetic and pharmacodynamic analysis of 5α-reductase inhibitors and androgens by liquid chromatography tandem mass spectrometry

AbstractBenign prostatic hyperplasia and prostate cancer can be treated with the 5α-reductase inhibitors, finasteride and dutasteride, when pharmacodynamic biomarkers are useful in assessing response. A novel method was developed to measure the substrates and products of 5α-reductases (testosterone, 5α-dihydrotestosterone (DHT), androstenedione) and finasteride and dutasteride simultaneously by liquid chromatography tandem mass spectrometry, using an ABSciex QTRAP® 5500, with a Waters Acquity™ UPLC. Analytes were extracted from serum (500µL) via solid-phase extraction (Oasis® HLB), with 13C3-labelled androgens and d9-finasteride included as internal standards. Analytes were separated on a Kinetex C18 column (150×3mm, 2.6µm), using a gradient run of 19min. Temporal resolution of analytes from naturally occurring isomers and mass +2 isotopomers was ensured. Protonated molecular ions were detected in atmospheric pressure chemical ionisation mode and source conditions optimised for DHT, the least abundant analyte. Multiple reaction monitoring was performed as follows: testosterone (m/z 289→97), DHT (m/z 291→255), androstenedione (m/z 287→97), dutasteride (m/z 529→461), finasteride (m/z 373→317). Validation parameters (intra- and inter-assay precision and accuracy, linearity, limits of quantitation) were within acceptable ranges and biological extracts were stable for 28 days. Finally the method was employed in men treated with finasteride or dutasteride; levels of DHT were lowered by both drugs and furthermore the substrate concentrations increased